MOolecular mechanism of senile dementia. -summary of research-

老年痴呆的分子机制。

基本信息

批准号：
04268104
负责人：
TATEISHI Jun
金额：
$ 106.43万
依托单位：
KYUSHU UNIVERSITY
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research on Priority Areas
财政年份：
1992
资助国家：
日本
起止时间：
1992 至 1995
项目状态：
已结题

项目摘要

We studied molecular mechanisms of neurodegenerative processes of aged brains and Alzheimer's disease (AD).Neurotrophic factors including nerve growth-factor (NGF) and its families such as BDNF,NT-3,4,5 and their reseptors (Trk, A,B,C) were studied at molecular and protein levels. Highly sensitive methods to detect these substances using specific antibodies were introduced. A novel cell adhesion molecule, gicerin was cloned and disclosed to act as neurite outgrowth factor. A growth inhibitory factor, GIF is a metallothionein-like protein and deficient in AD brains.Two abnormal structures in AD ; senile plaques and neuro-fibrrillary tangle-paired herical filaments (PHF) were analyzed through each constituents-Abeta and tau proteins. Proteolytic processing, modification and metabolism of these proteins were studied. Abeta protein with 1-42(43) residues exists mainly in inmature, diffuse plaques, while 1-40 in plaque cores and amyloid angiopathy. Cultured neural cells with high copy numbe … More rs of Abeta precursor protein (APP) gene died earlier from toxicity of APP.PHF is mainly composed of abnormally phosphorylated tau protein which is induced by tau protein kinase (TPK) I and II.Each kinase was disclosed to be a glycogen synthase kinase 3 (GSK 3) and cyclin-dependent kinase 5 (CDK 5), respectively. Ultrastructural and functional analyzes of motor molecules in nerve cell processes were disclosed by our members.Molecular genetic studies on AD were done concerning chromosomes 14,19 and 21. Gene locus of the early onset familial AD in Japan was suspected within 8cM length in chromosome 14 which was finally corresponded to presenilin I (S182) gene reported by Sherrington et al. The E4 isofprm of apolipoprotein E (Apo E) which gene locates on chromosome 19 was related with late and early onset AD,not only of familial but sporadic patients in Japan. A point mutation at codon 717 of APP gene on chromosome 21 was also proved in a few Japanese families. A not I restriction map of the entire long arm of human chromosome 21 was lately reported by our members Less

我们研究了老年大脑和阿尔茨海默病（AD）神经退行性过程的分子机制。神经营养因子包括神经生长因子（NGF）及其家族如BDNF、NT-3、4、5及其受体（Trk、A、B），C）在分子和蛋白质水平上进行了研究，引入了使用特异性抗体检测这些物质的高灵敏度方法，克隆并公开了一种新的细胞粘附分子，其可充当神经突的生长。 GIF 是一种生长抑制因子，是一种金属硫蛋白样蛋白，在 AD 大脑中缺乏。研究了这些具有1-42(43)残基的Abeta蛋白的蛋白水解加工、修饰和代谢。斑块，而斑块核心和淀粉样血管病中的 1-40 个具有高拷贝数的 Abeta 前体蛋白 (APP) 基因的培养神经细胞会因 APP 的毒性而较早死亡。PHF 主要由诱导的异常磷酸化 tau 蛋白组成。 tau 蛋白激酶 (TPK) I 和 II。每种激酶被公开为糖原合酶激酶 3 (GSK 3) 和细胞周期蛋白依赖性激酶 5 (CDK我们的成员分别公开了神经细胞突起中运动分子的超微结构和功能巢。对14、19和21号染色体进行了AD的分子遗传学研究。怀疑日本早发家族性AD的基因位点。 14号染色体上的8cM长度最终对应于Sherrington等人报道的早老素I（S182）基因。载脂蛋白E（Apo E）的E4 isofprm，其位于19号染色体上的APP基因与晚期和早期发病的AD有关，不仅在日本的家族性患者中而且在散发性患者中，21号染色体上的APP基因密码子717处的点突变也在一些日本家庭中得到证实。我们的成员最近报告了人类 21 号染色体整个长臂的变化 Less